Personalized medicine is a relatively young field of healthcare that aims at identifying each patient's genetic, genomic, and clinical information which allows making accurate individualized predictions of the likelihood of developing a given disease, prognosis of the disease, and susceptibility to therapy. Thus, personalized medicine enables making more informed medical decisions, choosing better-targeted therapies, and reducing healthcare costs.
Gliomas are a broad category of primary brain and spinal cord tumors with tumor cells that display characteristics of glial cells and constituting about 42% of all brain tumors. According to the American Cancer Society, gliomas can be divided into three subtypes, namely astrocytomas, oligodendrogliomas, and epedymomas, depending on the type of glial cells affected. Astrocytomas arise from astrocytes and make up about 35% of all brain tumors. Generally, astrocytomas are not curable because they spread all through the normal brain tissue. Astrocytomas are usually classified as low grade, intermediate grade, or high grade, on the basis of a microscopic examination of a biopsy sample, depending on criteria used by a doctor examining the biopsy under a microscope. The highest grade of astrocytomas is called glioblastomas the most common adult malignant brain tumor. The average survival of patients with glioblastoma multiforme (GBM) is less than 14 months after diagnosis.
Owing to the heterogeneous genomic landscape of gliomas, future therapies are likely to require personalization for each patient's tumor genotype and proteomic profile. In fact, patients with oligodendrogliomas have already benefited from personalized medicine as there is a clear relationship between response to chemotherapy and chromosomal profile (Cairncross et al., J. Natl. Cancer Inst., 1998, 90: 1473-1479).
Protein phosphatase methyltransferase 1 (PME-1) has been identified as a cancer-associated protein whose expression correlates with the progression of low-grade astrocytic gliomas to malignant glioblastomas (GBMs) (Puustinen et al., Cancer Res. 2009, 69: 2870-2877). PME-1 interacts with protein phosphatase 2A (PP2A), the inhibition of which is a prerequisite for human cell transformation (reviewed in Westermarck and Hahn, Trends Mol. Med., 2008, 14: 152-160). It has been suggested that PME-1 inhibits PP2A activity via its enzymatic methylesterase activity required for demethylation of the conserved leucine 309 on catalytic PP2Ac subunit (Janssens et al., Trends Biochem. Sci., 2008, 33:113-21). An alternative mechanism of inhibition has been proposed on the basis of structural analysis of PME-1-PP2A complex demonstrating that PME-1 directly binds to catalytic cleft of the PP2Ac subunit (Xing et al., Cell, 2008, 133:154-163). Nevertheless, the role of PME-1 in the development of gliomas and their chemoresistance is yet to be determined.
Although recent studies have found some candidate molecules as possible future targets for personalized therapeutics in the treatment of gliomas, there is also an identified need for identification and elucidation of markers that can be used to differentiate patients who a likely to benefit from chemotherapy from those who are not likely to respond to said therapy.